Multiple sclerosis (MS) is an immune-mediated syndrome of unknown etiology that affects 400,000 Americans, causes demyelination and axonal loss, and results in substantial neurological disability. We will use mice in which we have induced a chronic form of experimental autoimmune encephalomyelitis (EAE) to evaluate the general hypothesis that Ca2+-permeable ionotropic glutamate receptors (iGluRs) substantially influence the severity and prognosis of EAE and MS. Genetically manipulating iGluR subunit compositions in these mice will enable us to make extended in vivo observations of the effects of well defined changes in iGluR Ca2+ permeability on axonopathy and oligodendropathy during EAE, and on developmental and regenerative oligodendrogenesis. Success in these studies will: a) enhance understanding of the importance of excitotoxicity mediated by Ca2+-permeable iGluRs in destroying axons and oligodendroglia in EAE, thus providing information important in the design of new therapies for progressive MS;and b) for the first time permit extended in vivo analysis of the long-term effects of signaling by glutamatergic axons to the oligodendroglial lineage on oligodendrogenesis and myelination. PUBLIC HEALTH RELEVANCE: Multiple sclerosis is an immune-mediated syndrome of unknown etiology that affects 400,000 Americans, causes demyelination and axonal loss, and results in substantial neurological disability. By genetic manipulations of mice in which we induce an autoimmune inflammatory white matter disease closely resembling progressive multiple sclerosis, we will evaluate the contributions of excitotoxicity mediated by calcium-permeable ionotropic glutamate receptors to the destruction of axons and myelin-synthesizing oligodendroglia. These studies may suggest effective new avenues of therapy for progressive multiple sclerosis.